Our primary aim is the development of a coordinated set of new reagents for peptide synthesis, comprising new amide forming reagents, protective groups which can be removed under exceedingly mild conditions, and protective groups which can be used to achieve affinity isolation and solubilization. Primary approaches to amide formation include safety-catch activation and prior amine capture. Independently usable affinity isolation procedures or "handles" are to be used to achieve isolation and purification of products from coupling reactions without recourse to chromatography or crystallization. Protective groups are sought which can be removed with special reagents under conditions close to physiological minimizing damage to peptide products. Our new approach to amide formation involves prior thiol capture of an N-terminal cysteine residue of a peptide fragment, followed by intramolecular acyl transfer. In its most efficient form this strategy minimizes the need for protective groups and is therefore ideally suited to semisynthesis. Syntheses and semisyntheses of bovine pancreatic trypsin inhibitor and a series of analogs are described.